REVIEW

Korean J Intern Med 2016;31:210-218

http://dx.doi.org/10.3904/kjim.2015.137

Current concepts in the management of rheuma-

toid arthritis
Yoshiya Tanaka

The First Department of Internal Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by in-
Medicine, School of Medicine, flammation and joint destruction that causes significant morbidity and mortality.
University of Occupational and
Environmental Health, Japan, However, the combined use of methotrexate, a synthetic disease-modifying anti-
Kitakyushu, Japan rheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of
RA. Clinical remission is now realistic targets, achieved by a large proportion of
RA patients, and rapid and appropriate induction of remission by intensive treat-
ment with biological DMARD and methotrexate is prerequisite to halt joint dam-
age and functional disabilities. However, biological DMARD is limited to intra-
venous or subcutaneous uses and orally available small but strong molecules have
been developed. Oral administration of tofacitinib targeting the Janus kinase
(JAK) is significantly effective than placebo in active patients with methotrexate-
nave, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-
inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor.
Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under
debate and further investigation on post-marketing survey would be warranted.
On the other hand, discontinuation of a biological DMARD without disease flare
Received : April 30, 2015 is our next goal and desirable from the standpoint of risk reduction and cost ef-
Accepted : June 30, 2015
fectiveness, especially for patients with clinical remission. Recent reports indicate
Correspondence to that more than half of early RA patients could discontinue TNF-targeted bio-
Yoshiya Tanaka, M.D. logical DMARD without clinical flare and functional impairment after obtain-
The First Department of ing clinical remission. Contrarily, for established RA, fewer patients sustained
Internal Medicine, School of
Medicine, University of Occu- remission after the discontinuation of biological DMARD and deep remission
pational and Environmental at the discontinuation was a key factor to keep the treatment holiday of biological
Health, Japan, 1-1 Iseigaoka, DMARD.
Kitakyushu 807-8555, Japan
Tel: +81-93-603-1611
Fax: +81-93-691-9334 Keywords: Arthritis, rheumatoid; Antirheumatic agents; Biological antirheumatic
E-mail: tanaka@med.uoeh-u.ac.jp agents; Remission; Janus kinase inhibitor

INTRODUCTION T cells and inflammatory cytokines such as tumor ne-

Rheumatoid arthritis (RA) is a representative systemic
autoimmune disease characterized with chronic and
destructive inflammatory synovitis and multiple organ
manifestations that causes severe disability and mortal-
ity. It affects from 0.5% to 1.0% of adults with a 4-fold
higher frequency in women than in men. Auto-reactive
crosis factor (TNF) and interleukin 6 (IL-6) play a pivotal
role in the pathological processes of RA through the ac-
cumulation of inflammatory cells, the self-perpetuation
of inflammation, and production of matrix metallopro-
teinase and induction and/or activation of osteoclasts,
leading to destruction of cartilage and bone [1-3]. It is
noteworthy that such a joint damage derived from sy-

Copyright 2016 The Korean Association of Internal Medicine pISSN 1226-3303

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ eISSN 2005-6648
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http://www.kjim.org
Tanaka Y. Management of RA
novial inflammation is apparent in the early stage of the
disease. It is required to treat patients at a stage when
the evolution of joint destruction can still be prevented.
However, the combined use of methotrexate, a stan-
dard synthetic disease-modifying anti-rheumatic drug
(DMARD) and a biological DMARD targeting TNF, IL-
6, and T cells has revolutionized treatment of RA. Cur-
rently, clinical remission or low disease activity are now
realistic targets for the treatments, achieved by a large
proportion of RA patients. Also, it has been recognized
that early therapeutic intervention targeting remission
improves clinical outcomes and reduces the accrual and
progress of joint damage and disability. Furthermore,
the maintenance of remission, especially with biologi-
cal DMARD, leads to long-term structural and func-
tional remission. Thus, the combinational application
of methotrexate and biological DMARD has brought
about a paradigm shift in the management of RA and
the treatment target of RA has evolved to not only clini-
cal remission but also structural remission and func-
tional remission.
THE CURRENT CONCEPT OF TREATMENT OF
RA AND ITS PARADIGM SHIFT BY BIOLOGICAL
DMARD
Recent progress in the treatment of RA has changed di-
agnosis of RA [4]. The 2010 Rheumatoid Arthritis Classi-
fication Criteria was published by collaborative initiative
of an American College of Rheumatology (ACR)/Europe-
an League Against Rheumatism (EULAR). The new clas-
sification system redefines the current paradigm of RA
as arthritis at high risk of chronicity and erosive damage
by focusing on features at earlier stages of disease that
are associated with the definition. By the new diagnos-
tic system, it has become possible to treat patients with
synthetic DMARD such as methotrexate at an early stage
when evolution of joint destruction can still be pre-
vented or minimized. Actually it has proven that early
therapeutic intervention using synthetic DMARD and
biological DMARD not only improves clinical outcomes
but also reduces the occurrence of joint damage and dis-
ability [1-5].
From the global evidence, the treatment with meth-
otrexate and TNF inhibitors including infliximab,
http://dx.doi.org/10.3904/kjim.2015.137
etanercept, adalimumab, golimumab, and certolizumab
or a IL-6-receptor inhibitor such as tocilizumab leads to
clinical remission in approximately 30% to 60% of RA
patients. Effective treatments using TNF-inhibitors have
led to more stringent criteria for the clinical remission.
Furthermore, induction and/or maintenance of clinical
remission with TNF inhibitors and methotrexate can
potentially lead to reduction of radiographic progress in
joint destruction and improvement and keep of phys-
ical functions and abilities. For instance, structural re-
mission defined with yearly changes of modified total
Sharp score (mTSS) can be achieved in approximately
60% to 90% of patients treated with any TNF-inhibitors
and methotrexate. Furthermore, recent evidence shown
by clinical studies such as OPTIMA (Optimal Proto-
col for Treatment Initiation with Methotrexate and
Adalimumab) and HOPEFUL (adalimumab, a human
anti- TNF monoclonal antibody, outcome study for the
persistent efficacy under allocation to treatment strat-
egies in early RA), indicate that the delayed addition of
TNF-inhibitors to methotrexate-nave, early RA patients
did not impact clinical and functional outcomes at week
52, compared to the earlier addition of TNF-inhibitors
[6,7]. However, the occurrence of significant structural
damage during methotrexate mono-therapy period (the
first 26 weeks) contributed to the persistence of differ-
ences between the treatment strategies. These results
underscore the irreversible nature of erosive bone and
cartilage loss present in RA patients. From these results,
RA patients at risk for aggressive disease should benefit
from the early and intensive intervention with combina-
tion therapy of methotrexate and TNF inhibitors.
Thus, clinical remission has become a goal to be tar-
geted in the treatment of RA. A committee of ACR/EU-
LAR also provided new remission criteria that is strin-
gent but achievable and can be applied using outcome
composite measures to predict later good radiographic
and functional outcomes [8]. The new remission criteria
are defined by simplified disease activity index, clinical
disease activity index, and Boolean definition. Further-
more, a treat to target approach making good outcomes
and remission as the target for treatment have been
published based on accumulated background informa-
tion in terms of management of RA by an international
task force (Fig. 1) [5]. Thus, clinical remission has recent-
ly become an achievable goal in many patients and rapid
www.kjim.org 211

and appropriate induction of remission is prerequisite
to halt joint damage and functional disabilities, which
revealed improved outcomes with strategic therapeutic
approaches.
Once clinical remission is obtained, the remission has
to be maintained. The maintenance of the remission is
also applied to the treatment with biological DMARD.
The most important study regarding maintenance of
TNF-inhibitors was reported by Weinblatt et al. [9].
Etanercept, a TNF inhibitor, maintained disease activ-
ity and functional abilities beyond 10 years of therapy in
both early RA and longstanding RA patients; a total of
163 of 558 early RA patients and 264 of 714 longstanding
RA patients followed through year 10. Improvements in
ACR20, ACR50, and ACR70 responses, ratio of achieving
remission defined as a disease activity score 28 (DAS28) <
2.6 and reduction in Health Assessment Questionnaire
disability index score were maintained during the 10-
year period in the early RA patients as well as the long-
standing RA patients. During 11 years, five opportunistic
infections and 21 cases of sepsis were reported and oc-
currence of all malignancies was similar to that expected
in the general population, but the occurrence of lym-
phomas (n = 14) was higher than expected in the general
population. Thus, maintenance of functional ability and
inhibition of structural changes in joints have become
a long-term outcome of the treatment of RA using bio-
logical DMARD and methotrexate.
SDAI = SJC28 + TJC28 + PGA + EGA + CRP (mg/dL) CDAI = SDAI CRP
26.0 High disease activity 22.0
11.025.9 Intermediate disease activity 10.021.9
3.310.9 Low disease activity 2.89.9
3.3 Remission 2.8
Figure 1. Composite measures of disease activity: simplified
disease activity index (SDAI) and clinical disease activity in-
dex (CDAI) and remission criteria using SDAI or CDAI. SJC,
swollen joint count; TJC, tender joint count; PGA, patients
global health assessment (010.0 cm visual analogue scale
[VAS]); EGA, evaluators global health assessment (010.0 cm
VAS); CRP, C-reactive protein.
212 www.kjim.org
The Korean Journal of Internal Medicine Vol. 31, No. 2, March 2016
High disease activity
Intermediate disease activity
Low disease activity
Remission
THE NEXT DEVELOPMENT OF TREATMENT OF
RA: ORAL KINASE INHIBITORS
Although biological DMARDs have brought about para-
digm shift in the treatment of RA, only subcutaneous or
intravenous administration is allowed for their use be-
cause of their size the agents, which is reported 90,000
to 150,000 Dalton. Due to the size, these agents only
inhibit or activate intracellular interaction by binding
to cytokines or cell surface functional molecules such
as cytokine receptor or co-stimulatory molecules. Oral-
ly available low molecular weight products, targeting
key molecules during the disease processes; therefore,
currently attract particular attention because they en-
ter into cytoplasm and directly regulate intracellular
signals. Among them, products targeting kinase pro-
teins have been emerging because multiple signaling
kinases are involved in the pathological processes. The
multiple cytokines and cell surface molecules bind to
receptors, resulting in the activation of various signal-
ing, including phosphorylation of kinase proteins. Five
hundred and eighteen genes encoding kinase proteins
have been identified from human genome-wide stud-
ies. Among them, the tyrosine kinase is phosphorylated
following receptor binding in a cytokine response and
is involved in cell proliferation, differentiation and ad-
hesion during pathological processes including those
of RA. Therefore, many investigators have shed light on
tyrosine kinases as the target of the treatment of various
diseases. More than 90 genes encoding tyrosine kinases
have been identified from human genome-wide stud-
ies and 14 tyrosine kinases are known to be involved in
synovial membrane in patients with RA, compared to
those with osteoarthritis [10].
Among them, members of Janus kinase (JAK) family
are essential for the signaling pathways of various cy-
tokines and are implicated in the pathogenesis of RA.
Molecules in a JAK family consist of homodimer or
heterodimer of Jak1, Jak2, Jak3, and tyrosine kinase 2
(Tyk2). After the engagement of cytokines receptors
constitutively bound to JAK, JAK is activated by a con-
formational change and phosphorylated (Fig. 2). These
in turn phosphorylate the cytokine receptors, which
leads to phosphorylation of the signal transducers and
activators of transcription that subsequently translocate
into the nucleus, where they regulate gene expression.
http://dx.doi.org/10.3904/kjim.2015.137
Tanaka Y. Management of RA

IL-2, IL-4, IL-7 IL-4, IFN- IL-23 EPO, TPO, GM-CSF

IL-9, IL-15, IL-21 G-CSF IL-12 IL-3, IL-5, leptin than placebo with or without methotrexate in RA pa-
tients with methotrexate-nave, inadequately responsive
c
to methotrexate or inadequately responsive to TNF-in-
Stat
P P
hibitors. The efficacy occurred rapidly and strongly and
P P
there was not significant difference between tofacitinib

Tyk2
Jak1

Jak2
Jak1
Jak3

Jak2
Jak2
Jak2
P P P P P P P P and adalimumab, a representative TNF-inhibitor. Also,
P P P P P P
it is worth noting that significant improvement in 6
P P
months-changes of mTSS, erosion score, joint space
Stat3,5,6,1
Stat3,5,6,1

Tofacitinib

Stat3,5
Stat3,5
Stat4,3
Stat4,3
Stat1,3
Stat1,3
(CP-690,550)
narrowing score was observed in patients treated with 10
mg of tofacitinib, compared to placebo, indicating that
Transcription
IFN-, IL-17, IL-6 tofacitinib has a potential to inhibit progress in joint de-
struction in patients with RA.
Figure 2. Signaling mechanisms through the Janus kinase The most commonly reported adverse events were
(JAK)/STAT pathway and action point of a JAK inhibitor
tofacitinib. IL, interleukin; IFN, interferon; G-CSF, granu- infections such as nasopharyngitis, increases in total
locyte colony stimulating factor; EPO, erythropoietin; TPO, cholesterol, elevation of transaminase and serum creati-
thrombopoietin; GM-CSF, granulocyte-macrophage colony- nine, decreases in neutrophil counts and anemia [17-23].
stimulating factor.
Although the majority of the adverse events have been
tolerable and managed, opportunistic infections such
as herpes zoster disseminated, pulmonary tuberculosis,
Among members of a JAK family, the expression of JAK3 cryptococcal pneumonia and pneumocystis pneumoni-
is limited to lymphocytes and constitutively binds to the tis were reported. In our in vitro studies, proliferation
commonchain which is a common receptor subunit of CD4+ T cells in patients with RA stimulated with
for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 [11]. Therefore, anti-CD3 and anti-CD28 antibodies was significantly
the deficiency or dysfunction of Jak3 is synonymous reduced at week 52 after the tofacitinib treatment, com-
with impairment in these cytokines which impaired pared to that at the baseline, although no significant de-
lymphocyte development and function and leads to im- crease in CD4+ T cell count was observed, indicating the
munodeficiency in mice. However, because of its limit- possible relevance of the impairment in T cell respon-
ed expression on hematopoietic cells, the lack of Jak3 is siveness by tofacitinib to the serious infectious events
not known to affect other organs, whereas the deficiency [24]. Thus, although tofacitinib is approved in United
of Jak1 or Jak2 results in fetal death. Thus, selective inhi- States, Japan, Switzerland and many countries except
bition of Jak3 was considered as a potential target in the for the European Union, careful post-marketing surveil-
treatment of RA without affecting other organ systems lances would be required to pay special attention on in-
[12-14]. fections and malignancies and the accumulation of ev-
Based on these backgrounds, an orally available Jak idence regarding long-term safety would be warranted.
inhibitor tofacitinib was developed with expectations Although the precise action of tofacitinib on JAK
to be a new immunosuppressant with a few side effects. pathway in mice has been investigated, the exact mecha-
Tofacitinib was found by screening for inhibitors of in nism of action in patients with RA remained unclear.
vitro Jak3 kinase activity from the Pfizer chemical library Ghoreschi et al. [25,26] reported that tofacitinib potently
and extensive chemical modification by Changelian et inhibited Jak3 and Jak1 and to a lesser extent Jak2 with
al. [15], Flanagan et al. [16]. Thereafter, multiple clinical little effects on Tyk2 and that it, thereby, inhibited sig-
trials using an orally available JAK inhibitor tofacitinib naling by interferon (IFN-), IL-6 and to a lesser extent
for patients with RA have been globally undertaken. IL-12 and IL-23, indicating that Th1 cell differentiation
Subsequently to multiple phase 2 trials, 6 phase 3 studies is therefore blocked, as is the generation of patho-
were performed to investigate the efficacy and safety of genic Th17 cells. We also assessed the in vivo effects of
tofacitinib [17-23]. Briefly, oral administration of 5 or 10 tofacitinib using the severe combined immune defi-
mg twice a day of tofacitinib was significantly effective ciency (SCID)-human rheumatoid arthritis-transgenic

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(HuRAg) mice, an RA animal model utilizing SCID
mice implanted with synovium and cartilage from pa-
tients with RA and tofacitinib was continuously given
to the mice by the osmotic mini-pump [27]. Treatment
of SCID-HuRAg mice with tofacitinib suppressed IL-17
and IFN- production and proliferation of CD4+ T cells,
resulting in inhibition of IL-6 and IL-8 production by
synovial fibroblasts and CD14+ cells as well as cartilage
destruction. We also clarified that tofacitinib inhibited
differentiation and antibody production of B cells as
well as antigen-presentation activity of dendritic cells
by inhibiting type I IFN-mediated signaling and subse-
quently reducing expression of costimulatory molecules
such as CD80 and CD86 [28,29]. Taken together, primary
targets of tofacitinib appear dendritic cells, CD4+ T cells
and activated B cells which leads to multi-cytokine tar-
geting beyond simply a JAK3 inhibitor.
According to the launch of tofacitinib, although there
are long-term safety concerns, multiple low molecular
weight products targeting JAK are emerging for the de-
velopment (Fig. 3). The JAK3 inhibitors decernotinib and
peficitinib showed strong and rapid efficacy and similar
adverse events to tofacitinib in their phase 2 trials. Phase
2 clinical trials were over regarding baricitinib targeting
JAK1/2 and filgotinib targeting JAK1 and similar effica-
cy were reported. Thus, orally available small molecules
targeting specific kinase could represent a valuable ad-
dition to the current DMARD and biologic agents and
JAK3
JAK1
Baricitinib
Filgotinib c-Family
IL-2, IL-4
JAK2 IL-7, IL-9
Type II IFN IL-15, IL-21
IFN-
c Family gp130 family
IL-3, IL-5, GM-CSF IL-6, LIF, OSM Type I IFNs
Homodimeric IL-10 family IFN-, IFN-
receptor family IL-10, IL-19
growth hormone, IL-20, IL-22
EPO, TPO
IL-12 family
IL-12, IL-23
TYK2
Figure 3. Development of Janus kinase (JAK) inhibitors. IL,
interleukin; IFN, interferon; LIF, leukemia inhibitory factor;
OSM, oncostatin M; EPO, erythropoetin; TPO, thrombopo-
etin; TYK, tyrosine kinase.
214 www.kjim.org
The Korean Journal of Internal Medicine Vol. 31, No. 2, March 2016
these kinase inhibitors such as Jakinibs would take in
the therapeutic armamentarium in RA and multiple au-
toimmune diseases.
THE NEXT DEVELOPMENT OF TREATMENT OF
RA: DRUG HOLIDAY
After clinical remission is obtained by DMARD and/or
biological DMARD, the remission has to be maintained.
The 8th recommendation in the treat-to-target is that
the desired treatment target should be maintained
throughout the remaining course of the disease [5].
However, biological DMARDs are also associated with
short and long-term adverse effects including injec-
tion site reactions, increased risk of infection and high
costs. Optimal use of these drugs is therefore warranted,
including the right dose for the right patient. Effective
dose reduction in the context of low disease activity is;
however, up to recently very uncommon in daily clini-
cal practice. Currently, discontinuation of a biological
DMARD without disease flare is our next goal and de-
sirable from the standpoint of risk reduction and cost
effectiveness, especially for patients with clinical remis-
sion. Thus, how and when biological DMARDs are re-
escalated without disease flare is an emerging theme to
strategically treat RA. We are now in a position to evalu-
ate what is possible in terms of maintaining remission
while at the same time reducing the burden of treat-
ment on the patient and health care system. Currently,
data are emerging from large, well-conducted studies
designed to answer this question, shedding light on
Tofacitinib which patient populations and treatment strategies can
Decernotinib
Peficitinib survive treatment discontinuation or tapering with low
risk of disease flare without functional and radiographic
damage progression [30-32].
Data emerging from large, well-conducted studies
indicate that approximately half of early RA patients
could discontinue biological DMARDs targeting TNF
without clinical flare and functional impairment after
obtaining reduction of disease activity to remission by
biological DMARDs in combination with methotrexate.
For instance, a multinational, double-blinded, random-
ized controlled study, OPTIMA study, was performed to
determine the optimal protocol for treatment initiation
with adalimumab plus methotrexate in patients with RA
http://dx.doi.org/10.3904/kjim.2015.137
Tanaka Y. Management of RA

[6]. In this study, the withdrawal of adalimumab in early
RA patients with a mean RA duration of 3.9 months was
also assessed. Outcomes of withdrawal or continuation
of adalimumab were assessed in patients who achieved a
stable low disease activity target after 26 weeks of initial-
ly assigned treatment with adalimumab and methotrex-
ate. Of the 466 RA patients treated with adalimumab and
methotrexate, 207 achieved the stable low disease activ-
ity measured by DAS28-C-reactive protein at weeks 22
and 26 and were re-randomized to placebo plus meth-
otrexate or adalimumab plus methotrexate during the
second study period for 52 weeks. After 52 weeks, 91%
and 86% of patients who continued adalimumab treat-
ment maintained low disease activity and remission,
respectively, compared with 81% and 66% of patients
who withdrew from adalimumab treatment. Saleem et
al. [33] also reported that a TNF-inhibitor-free sustained
remission rate was 60% after acquiring DAS28 remis-
sion in methotrexate-nave early RA patients. Within the
initial treatment group, the only clinical predictor of the
successful discontinuation was shorter symptom dura-
tion prior to receiving therapy (median, 5.5 months vs.
9.0 months, p = 0.008). No other clinical features includ-
ing activity measured by power Doppler were associated
with the discontinuation of biological DMARD.
However, fewer patients sustained remission or low
disease activity after the discontinuation of biological
DMARDs for patients with established RA, compared to
early RA. It is often difficult to successfully discontinue
biological DMARDs and the results were controversial
among studies. For instance, we carried HONOR study
to investigate the possibility of discontinuing adalim-
umab for 1 year without flaring in RA patients [34]. Prior
to the study, 197 RA patients with inadequate response
to methotrexate were treated with methotrexate and
adalimumab and 75 patients met the adalimumab-free
criteria, steroid-free, and sustained DAS28-erythrocyte
sedimentation rate (ESR) remission for more than 6
months (Fig. 4). The mean disease duration and DAS28-
ESR score in 75 patients was 7.5 years and 5.1 at baseline,
respectively. Of the 75 patients, 52 agreed to adalimumab
discontinuation and 23 patients continued to use adali-
mumab for 1 year. The remission rate (83%) and the
rates of low disease activity (91%) measured by DAS28-
ESR in the adalimumab continuation group were sig-
nificantly higher than those (48% and 62%, respectively)
in the adalimumab discontinuation group 1 year after
the continuation or discontinuation decision was made.
In the analysis of predictive factors related to sustaining
remission for 1 year, DAS28-ESR at the discontinuation
and disease duration had a marked correlation with
sustained remission in multivariate analyses. Patients
whose disease duration was less than 2 years, higher
ratio of remission and low disease activity were kept
at 1 year after the discontinuation than those with lon-
ger than 2 years (Fig. 5). Subsequent receiver operating
characteristic analysis for high estimation of sustained
remission indicated a cut-off value for the adalimum-

8 8
Sustained REM MTX treatment
7 7
ADA re-administration
Failed
6 6

5 5
DAS28-ESR

4 4
3.2
3 3
2.6
2 2

1 1

0 0
0 12 0 6
Time after ADA Time after the rescue of
Start
Discontinuation (mon) patients with flare (mon)
ADA

Figure 4. Clinical course of rheumatoid arthritis patients who discontinued adalimumab after obtaining clinical remission by
methotrexate and adalimumab. Adapted from Tanaka et al. [34]. DAS28, disease activity score 28; ESR, erythrocyte sedimenta-
tion rate; ADA, adalimumab; REM, remission; MTX, methotrexate.

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ab-free remission of 1.98, indicating that deep remis-
sion would be a key for successful discontinuation of
adalimumab in established patients with RA. The RRR
(remission induction by Remicade in RA) study was also
undertaken to assess the possibility of discontinuation
of infliximab DMARDs in established RA patients. This
study also indicated that deep remission is required to
successfully discontinue biological; DAS28-ESR cut-off
point at discontinuation was 2.22 for achieving low dis-
ease activity at week 52 in the infliximab-free group [35].
Thus, the mild remission is insufficient for the discon-
tinuation and biological DMARDs should be continued
in such patients even under DAS28 remission.
Thus, treatment holiday of biological DMARDs is
now feasible in some patients with RA with long-stand-
ing RA, but deep remission at the discontinuation is
a key factor to keep the treatment holiday of biological
DMARDs (Fig. 6) [30-32]. However, such intensive treat-
ment would have the potential of reducing drug-in-
duced adverse effects and reducing long-terms medical
costs, although the risks of worsening clinical, structur-
al, and functional outcomes should be considered with
careful monitoring.
CONCLUSIONS
RA is a systemic autoimmune disease, leading to synovi-
al hypertrophy and adjacent bone and cartilage destruc-
()
100 p0.05 p0.05
90
80 77.8
70 63.0
60
50
40 33.3
30
20
10
0
Remission Low disease activity
(DAS28-ESR < 2.6) (DAS28-ESR 3.2)
Early RA ( 2 yr, n = 27) Established RA (> 2 yr, n = 24)
Figure 5. %Remission and %low disease activity at 1 year
after discontinuation of adalimumab in patients with early
rheumatoid arthritis (RA) versus established RA. Adapted
from Tanaka et al. [34]. DAS28, disease activity score 28; ESR,
erythrocyte sedimentation rate.
216 www.kjim.org
The Korean Journal of Internal Medicine Vol. 31, No. 2, March 2016
tion that causes significant morbidity and mortality.
However, the combined use of synthetic DMARD such
as methotrexate and a biological DMARD targeting TNF
and IL-6 have revolutionized treatment of RA and clin-
ical remission or low disease activity are now realistic
targets, achieved by a large proportion of RA patients.
Furthermore, the maintenance of remission or low dis-
ease activity has produced significant improvements in
radiographic and function outcomes.
However, biological DAMRD requires special han-
dling and transport and parenteral administration. Even
with this outstanding effective drugs, there are portion
of patients that are still refractory to all existing biolog-
ics. Tofacitinib targets the JAK which plays pivotal roles
in the beginning of the intracellular cytokine signaling
pathway thereby inhibits multiple pathways. The mul-
tiple phase 3 studies revealed that and oral administra-
tion of 5 or 10 mg tofacitinib was significantly effective
than placebo with or without methotrexate in active RA
patients with methotrexate-nave, inadequately respon-
sive to methotrexate or TNF-inhibitors. Therapeutic ef-
ficacy of tofacitinib was observed in a short term after
administration in patients and was as strong as adalim-
umab, a TNF-inhibitor. The most commonly observed
adverse events were related to infection, hematologic,
hepatic, and renal disorders. Meanwhile, association of
tofacitinib on carcinogenicity is under debate. Further
investigation on post-marketing survey will greatly help
us understand the positioning of this drug.
Disease activity (DAS28, SDAI, HAQ-DI)
Remission Remission
induction maintenance
Before joint damage Maintenance, adherence
Intensive treatment Safety management
with methotrexate + Efficacy maintenance
45.8 biological DMARD De-escalation (glucocorticoid,
JAK inhibitors? methotrexate, tapering or
discontinuation of biological
DMARD)
0 0.5 10
Treatmend duration (yr)
Figure 6. Treatment strategy for rheumatoid arthritis to
stop joint damage. DAS28, disease activity score 28; SDAI,
simplif ied disease activity index; HAQ-DI, Health As-
sessment Questionnaire disability index; DMARD, dis-
ease-modifying anti-rheumatic drug; JAK, Janus kinase.
http://dx.doi.org/10.3904/kjim.2015.137
Tanaka Y. Management of RA
We also need to create the therapeutic strategies for
the long-term maintenance after obtaining remission
in order to keep structural remission, functional remis-
sion, social remission and comprehensive remission.
However, there are concerns regarding long-term safety
by using synthetic DMARDs as well as economic burden
associated with expensive biological DMARDs. Thus,
de-escalation of synthetic and/or biological DMARDs
attracts attention from the contexts. How and when
DMARDs are de-escalated without disease flare is an
emerging theme to strategically treat RA. Recent re-
ports indicate that more than half of early RA patients
could discontinue biological DMARD targeting TNF
after obtaining reduction of disease activity remission.
However, fewer patients sustained remission after the
discontinuation of biological DMARDs for patients with
established RA, but deep remission at the discontin-
uation is a key factor to keep the treatment holiday of
biological DMARD. However, such a treatment strate-
gy would have the potential of reducing drug-induced
adverse effects and reducing long-terms medical costs,
although the risks of worsening clinical, structural and
functional outcomes should be considered with careful
monitoring. Since we have obtained strong weapons to
treat RA, a new strategy rather than a new target should
be required for the advanced therapy of RA.
Conflict of interest
Y.T. has received consulting fees, speaking fees, and/
or honoraria from Abbvie, Chugai, Astellas, Takeda,
Santen, Mitsubishi-Tanabe, Pfizer, Janssen, Eisai, Dai-
ichi-Sankyo, UCB, GlaxoSmithKline, Bristol-Myersand
has received research grants from Mitsubishi-Tanabe,
Chugai, MSD, Astellas, Novartis. No funding was used
to support the writing of the manuscript.
Acknowledgments
The authors thank all medical staff in all institutions for
providing the data. This work was supported in part by
a Grant-In-Aid for Scientific Research from the Minis-
try of Health, Labor and Welfare of Japan, the Ministry
of Education, Culture, Sports, Science and Technology
of Japan, and the University of Occupational and Envi-
ronmental Health, Japan, through UOEH Grant for Ad-
vanced Research.
http://dx.doi.org/10.3904/kjim.2015.137
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